The voltage-gated calcium channel CaVa2d subunit is the site of action of two gabapentinoid drugs, gabapentin (Neurontin) and pregabalin (Lyrica), that are used to treat neuropathic pain, pain associated with fibromyaglia, migraine, epilepsy, and a number of mood disorders. Despite the direct connection between CaVa2d and the treatment of nervous system disorders, nothing is known about CaVa2d molecular structure at high resolution, the detailed molecular mechanisms by which CaVa2d affects voltage-gated calcium channel function, or how gabapentin and pregabalin bind to CaVa2d and modulate voltage-gated calcium channel activity. We seek to determine the high-resolution structure of CaVa2d and CaVa2d complexes with gabapentinoid drugs. Our efforts are directed at developing the appropriate expression systems to produce CaVa2d proteins for crystallographic study and to solve the high-resolution structure of CaVa2d. This work should unveil the fundamental structures that underlie CaVa2d function and reveal how gabapentinoid drugs interact with CaVa2d. This knowledge will bear directly on understanding the basic mechanisms of action of gabapentinoid drugs and should facilitate the development of better therapeutics that will improve the treatment of pain and a wide range of nervous system and mood disorders. PUBLIC HEALTH RELEVANCE: Voltage-gated calcium channels are the targets of drugs that are used to treat pain, epilepsy, migraine, fibromyalgia, and mood disorders. Our work aims to determine the molecular architecture that underlies how such drugs interact with and affect channel function. Such knowledge is indispensable for the improvement of current therapies and development of more efficacious treatments for a variety of nervous system disorders.